A major concern in the treatment of HIV/AIDS is the establishment of long-term cellular reservoirs where virus is maintained in a replication-competent form that perpetuates persisting infection. Much attention has been focused on latently infected CD4 T cells, and to a lesser extent monocytes/macrophages, however, little attention has been given to the follicular dendritic cell (FDC) reservoir of HIV even though it is one of the largest reservoirs in the body estimated to contain 1.5xl08 copies of viral RNA per gram of lymphoid tissue. Our working hypothesis is that FDCs are a long-term reservoir of infectious virus preserved in a microenvironment that is ideally organized for transmission and propagation of HIV. Our previous studies indicate that FDC-trapped HIV: i) is highly infectious and remains so even in the presence of potent neutralizing antibodies; and ii) is maintained in an infectious form for months with no requirement for active viral infection/replication. Progress during the last funding period indicated that FDCs contribute to a highly permissive microenvironment for virus transmission and propagation by: i) increasing the level of CXCR4 expression on surrounding germinal center (GC) CD4 T cells making them highly susceptible to infection with X4-tropic HIV; ii) producing chemokines (e.g. CXCL13) that attract GC T cells while providing signaling that inhibits migration away from the FDCs; and iii) increasing HIV transcription in a TNF dependent manner. We have also found that attempts to destroy the FDC reservoir of HIV by blocking signals needed for development and maintenance of FDCs fails to ablate this important source of infectious virus. This renewal application seeks to extend our studies on the FDC-HIV reservoir by: i) determining the genetic relatedness of FDC trapped virus in one secondary, lymphoid tissue site with that found in other sites sampled at the same time; ii) establishing the genetic relatedness of virus trapped on FDCs over time in the same patient; iii) characterizing FDC-HIV interactions that contribute to viral pathogenesis; and iv) identifying contributions of the FDC-GC microenvironment to HIV transmission and expression.